Theiler's virus infection is a new animal model of virus-induced demyelination characterized by a protracted course. Preliminary ultrastructural and immunopathologic studies of infected mice suggest an immunopathological mechanism of myelin degeneration. An analogous combined viral-immune pathogenesis has been also advocated by many in the human disease of multiple sclerosis. This important relation of Theiler's virus infection to M.S. stimulated the present project. The morphogenesis of demyelination will be followed ultrastructurally at different intervals after infection and will be compared to other known patterns of myelin break-down such as those in EAE, canine distemper, JHM virus encephalomyelitis and multiple sclerosis. Morphologic studies of immunosuppressed, suppressed and reconstituted mice and on recipients of either serum or lymphocytes from diseased animals will then be performed in order to clarify the effects of such immunologic manipulations on the production of lesions. These experiments are directed to a better understanding of the role played by immunologic mechanisms in the production of white matter lesions, and will be complemented by immunohistochemical studies with horseradish peroxidase as marker. Two different aspects will be studied, 1) The abundance of plasma cells in Theiler's infection, especially in latter stages of the disease, offers a good opportunity to investigate the presence of anti-viral and/or anti-myelin antibody in areas of demyelination. 2) As preliminary studies have failed to visualize viral particles in any cell type, a search for viral antigen by EM immunoperoxidase technique using labeled viral antibody will be carried out. Non-structural viral antigen could in part be responsible for an immune reaction against any cellular component which bears such antigen and only be uncovered by histochemical techniques.